Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane

ABSTRACT

Intermediates and processes are disclosed which are useful for the preparation of a substantially pure compound of the formula: ##STR1## wherein R 6  and R 7  are each hydrogen or R 6  and R 7  are independently selected from ##STR2## wherein R a  and R b  are independently selected from hydrogen, loweralkyl and phenyl and R c , R d  and R e  are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and ##STR3## wherein the naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo; or 
     R 6  is as defined above and R 7  is R 7a  OC(O)- wherein R 7a  is loweralkyl or benzyl; or 
     R 6  and R 7  taken together with the nitrogen atom to which they are bonded are ##STR4## wherein R f , R g , R h  and R i  are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl and R 8  is hydrogen or --C(O)R&#34; wherein R&#34; is loweralkyl, alkoxy, benzyloxy or phenyl wherein the phenyl ring is unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo; or an acid addition salt thereof.

This is a division of U.S. patent application Ser. No. 08/281,502, filedJul. 27, 1994, now U.S. Pat. No. 5,491,253, which is acontinuation-in-part of U.S. patent application Ser. No. 08/141,795,filed Oct. 22, 1993.

TECHNICAL FIELD

The present invention relates to intermediates and processes which areuseful for the preparation of a substituted 2,5-diamino-3-hydroxyhexane.

BACKGROUND OF THE INVENTION

Compounds which are inhibitors of HIV protease are useful for inhibitingHIV protease in vitro and in vivo and are useful for inhibiting an HIVinfection. Certain HIV protease inhibitors compose a moiety which is asubstituted 2,5-diamino-3-hydroxyhexane. HIV protease inhibitors ofparticular interest are compounds of the formula 1: ##STR5## wherein Ais R₂ NHCH(R₁)C(O)- and B is R_(2a) or wherein A is R_(2a) and B is R₂NHCH(R₁)C(O)- wherein R₁ is loweralkyl and R₂ and R_(2a) areindependently selected from --C(O)-R₃ -R₄ wherein at each occurrence R₃is independently selected from O, S and --N(R₅)- wherein R₅ is hydrogenor loweralkyl and at each occurrence R₄ is independently selected fromheterocyclic or (heterocyclic)alkyl; or a pharmaceutically acceptablesalt, prodrug or ester thereof. Compounds of formula 1 are disclosed inEuropean Patent Application No. EP0486948, published May 27, 1992.

A preferred HIV protease inhibitor of formula 1 is a compound of formula2a: ##STR6## or a pharmaceutically acceptable salt, prodrug or esterthereof.

Another preferred HIV protease inhibitor of formula 1 is a compound offormula 2b: ##STR7##

The compound of formula 2b is disclosed in PCT Patent Application No.WO94/14436, published Jul. 7, 1994, which is hereby incorporated hereinby reference.

An intermediate which is especially useful for preparing compounds ofthe formula 1 and 2 is a substantially pure compound of the formula 3:##STR8## wherein R₆, R₇ and R₈ are independently selected from hydrogenand an N-protecting group; or an acid addition salt thereof. PreferredN-protecting groups R₆ and R₇ are independently selected from ##STR9##wherein R_(a) and R_(b) are independently selected from hydrogen,loweralkyl and phenyl and R_(c), R_(d) and R_(e) are independentlyselected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo andphenyl; and ##STR10## wherein the naphthyl ring is unsubstituted orsubstituted with one, two or three substitutents independently selectedfrom loweralkyl, trifluoromethyl, alkoxy and halo.

Alternatively R₆ and R₇ taken together with the nitrogen atom to whichthey are bonded are ##STR11## wherein R_(f), R_(g), R_(h) and R_(i) areindependently selected from hydrogen, loweralkyl, alkoxy, halogen andtrifluoromethyl.

In addition, R₇ can be R_(7a) OC(O)- wherein R_(7a) is loweralkyl(preferably, t-butyl) or benzyl.

More preferred N-protecting groups R₆ and R₇ are those wherein R₆ and R₇are independently selected from benzyl and substituted benzyl whereinthe phenyl ring of the benzyl group is substituted with one, two orthree substituents independently selected from loweralkyl,trifluoromethyl, alkoxy, halo and phenyl. The most preferredN-protecting groups R₆ and R₇ are those wherein R₆ and R₇ are eachbenzyl.

Preferred N-protecting groups R₈ are --C(O)R" wherein R" is loweralkyl,alkoxy, benzyloxy or phenyl wherein the phenyl ring is unsubstituted orsubstituted with one, two or three substituents independently selectedfrom loweralkyl, trifluoromethyl, alkoxy and halo. A most preferredN-protecting group R₈ is t-butyloxycarbonyl.

Preferred intermediates of the formula 3 are the compounds wherein (i)R₆, R₇ and R₈ are each hydrogen or (ii) R₆ and R₇ are each benzyl orsubstituted benzyl wherein the phenyl ring of the benzyl group issubstituted with one, two or three substituents independently selectedfrom loweralkyl, trifluoromethyl, alkoxy, halo and phenyl, or R₆ and R₇taken together with the nitrogen atom to which they are bonded are##STR12## wherein R_(f), R_(g), R_(h) and R_(i) are independentlyselected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyland R₈ is hydrogen or t-butyloxycarbonyl or (iii) R₆ and R₇ are hydrogenand R₈ is tobutyloxycarbonyl.

DISCLOSURE OF THE INVENTION

The present invention relates to intermediates and processes for thepreparation of a substantially pure compound of the formula 3. A keyintermediate in the processes of the present invention is asubstantially pure compound of the formula 4: ##STR13## wherein R₆ andR₇ are independently selected from ##STR14## wherein R_(a) and R_(b) areindependently selected from hydrogen, loweralkyl and phenyl and R_(c),R_(d) and R_(e) are independently selected from hydrogen, loweralkyl,trifluoromethyl, alkoxy, halo and phenyl; and ##STR15## wherein thenaphthyl ring is unsubstituted or substituted with one, two or threesubstitutents independently selected from loweralkyl, trifluoromethyl,alkoxy and halo; or

R₆ is as defined above and R₇ is R_(7a) OC(O)- wherein R_(7a) isloweralkyl or benzyl; or

R₆ and R₇ taken together with the nitrogen atom to which they are bondedare ##STR16## wherein R_(f), R_(g), R_(h) and R_(i) are independentlyselected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyland R₈ is hydrogen or --C(O)R" wherein R" is loweralkyl, alkoxy,benzyloxy or phenyl wherein the phenyl ring is unsubstituted orsubstituted with one, two or three substituents independently selectedfrom loweralkyl, trifluoromethyl, alkoxy and halo; or an acid additionsalt thereof.

A preferred intermediate is the compound of formula 4 wherein R₆ and R₇are independently selected from benzyl and substituted benzyl whereinthe phenyl ring of the benzyl group is substituted with one, two orthree substituents independently selected from loweralkyl,trifluoromethyl, alkoxy, halo and phenyl and R₈ is hydrogen or --C(O)R"wherein R" is loweralkyl, alkoxy or phenyl wherein the phenyl ring isunsubstituted or substituted with one, two or three substituentsindependently selected from loweralkyl, trifluoromethyl, alkoxy andhalo.

A more preferred intermediate is the compound of the formula 4 whereinR₆ and R₇ are benzyl and R₈ is hydrogen or t-butyloxycarbonyl.

Another key intermediate in the processes of the present invention is asubstantially pure compound of the formula 6: ##STR17## wherein R₆ andR₇ are independently selected from ##STR18## wherein R_(a) and R_(b) areindependently selected from hydrogen, loweralkyl and phenyl and R_(c),R_(d) and R_(e) are independently selected from hydrogen, loweralkyl,trifluoromethyl, alkoxy, halo and phenyl; and ##STR19## wherein thenaphthyl ring is unsubstituted or substituted with one, two or threesubstitutents independently selected from loweralkyl, trifluoromethyl,alkoxy and halo; or

R₆ is as defined above and R₇ is R_(7a) OC(O)- wherein R_(7a) isloweralkyl or benzyl; or

R₆ and R₇ taken together with the nitrogen atom to which they are bondedare ##STR20## wherein R_(f), R_(g), R_(h) and R_(i) are independentlyselected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl;or an acid addition salt thereof.

A preferred intermediate is the compound of formula 6 wherein R₆ and R₇are independently selected from benzyl and substituted benzyl whereinthe phenyl ring of the benzyl group is substituted with one, two orthree substituents independently selected from loweralkyl,trifluoromethyl, alkoxy, halo and phenyl.

A more preferred intermediate is the compound of the formula 6 whereinR₆ and R₇ are benzyl.

A process for the preparation of 4 and 6 is shown in Scheme I.N-protection of L-phenylalanine (for example, R₆ and R₇ are both benzyl)and esterification (for example, R is loweralkyl or benzyl) providescompound 5. Reaction of 5 with the α-carbanion of acetonitrile in aninert solvent provides nitrile 6. Suitable inert solvents includeethereal solvents ( for example, tetrahydrofuran (THF), dimethoxyethane(DME), methyl tert-butyl ether (MTBE), diethyl ether and the like) or amixture of an ethereal solvent and a hydrocarbon solvent (for example,pentane, hexane, heptane and the like). A preferred solvent is aTHF/heptane mixture. The α-carbanion of acetonitrile can be prepared byreacting acetonitrile with bases such as sodium amide, potassiumt-butoxide, sodium hexamethyldisilazane, sodium hydride, lithiumdiisopropylamide, lithium diethylamide, n-BuLl and the like.Alternatively, reaction of 5 with the enolate of tert-butylcyanomalonate, followed by decarboalkoxylation, provides nitrile 6.Reaction of nitrile 6 with benzyl Grignard (for example, benzylmagnesiumchloride) provides enamine 4.

A process for the preparation of 3 from 4 is shown in Scheme II. In theprocess of Scheme II, if R₇ is R_(7a) OC(O)-, then R_(7a) is benzyl.Reaction of 4 with a borohydride reducing agent (for example, NaBH₄,NaBH₃ CN, LiBH₄, KBH₄, K(OiPr)₃ BH, Na(OMe)₃ BH and the like) in thepresence of a carboxylic acid (R₂₅ -COOH wherein R₂₅ is loweralkyl,haloalkyl, phenyl or halophenyl) in an inert solvent in a molar ratio ofenamine:reducing agent:carboxylic acid of 1: from about 1 to about 20:from about 1 to about 20 provides 7 (i.e., 3a wherein R₈ is hydrogen). Apreferred reducing agent is NaCNBH₃ and a preferred carboxylic acid istrifluoroacetic acid. A preferred ratio of enamine:reducingagent:carboxylic acid is 1: about 4: about 4. In this process, thereducing agent is added to a solution of the enamine, followed byaddition of the carboxylic acid.

An alternative process for the preparation of 3 from 4 involves aone-pot 2-step reaction sequence. In the first step of this alternativeprocess, the enamine is reacted with a boron-containing reducing agentwherein the reducing agent has first been reacted with an acid selectedfrom (i) R₂₆ -COOH wherein R₂₆ is loweralkyl, haloalkyl, phenyl orhalophenyl, (ii) R₂₇ -SO₃ H wherein R₂₇ is OH, F, loweralkyl, haloalkyl,phenyl, loweralkyl-substituted phenyl, halophenyl or naphthyl and (iii)R₂₈ -PO₃ H₂ wherein R₂₈ is OH, loweralkyl or phenyl or a combination ofsaid acids.

Examples of boron-containing reducing agents include borohydridereducing agents (for example, NaBH₄, NaCNBH₃, LiBH₄, KBH₄ and the like),boron-containing reducing agents such as 9-borabicyclo[3.3.1]nonane,(R)-B-isopinocampheyl-9-borabicyclo[3.3.1]nonane or(S)-B-isopinocampheyl-9-borabicyclo[3.3.1]nonane and the like, and BH₃complexes such as borane amine complexes (for example, borane-ammoniacomplex, borane-t-butylamine complex, borane-N,N-diethylaniline complex,borane-N,N-diisopropyl-ethylamine complex, borane-dimethylaminecomplex,4-(borane-dimethylamino)pyridine, borane-4-ethylmorpholinecomplex, borane-2,6-lutidine complex, borane-4-methylmorpholine complex,borane-morpholine complex, borane-4-phenylmorpholine complex,borane-piperazine complex, borane-piperidine complex,borane-poly(2-vinylpyridine) complex, boranepyridine complex,borane-pyrrole complex, borane-trimethylamine complex,borane-triethylamine complex and the like), borane ether complexes (forexample, borane-tetrahydrofuran complex and the like), a borane sulfidecomplex (for example, borane-methylsulfide complex, borane-1,4-oxathianeand the like) and borane phosphine complexes (for example,borane-tributylphosphine complex, borane-triphenylphosphine complex andthe like) and the like.

A preferred boron-containing reducing agent is a borohydride reducingagent. A preferred borohydride reducing agent is NaBH₄.

Examples of acids R₂₆ -COOH include acetic acid, propionic acid,trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid,difluoroacetic acid, benzoic acid and pentafluorobenzoic acid. Examplesof acids R₂₇ -SO₃ H include sulfuric acid, methanesulfonic acid,ethanesulfonic acid, trifluoromethanesulfonic acid, fluorosulfonic acid,phenylsulfonic acid and ptoluenesulfonic acid. Examples of acids R₂₈-PO₃ H₂ include phosphoric acid, methylphosphonic acid, ethylphosphonicacid and phenylphosphonic acid.

A preferred acid is R₂₇ -SO₃ H. A more preferred acid is methanesulfonicacid.

In the first step of the alternative process, the acid is added to theboron-containing reducing agent in an inert solvent. Then the enamine isadded to the boron-containing reducing agent/acid complex. In the firststep of the alternative process, the molar ratio of enamine: reducingagent: acid is 1: from about 1 to about 10: from about 2 to about 20.

In the first step of the alternative process, a preferred molar ratio ofenamine: reducing agent: acid is 1: from about 2 to about 4: from about4 to about 10. A most preferred molar ratio of enamine: reducing agent:acid is 1: about 2.5: about 6.

Suitable inert solvents for this process include alkyl- and aryl- ethersand polyethers such as tetrahydrofuran (THF), dimethoxyethane (DME),methyl tert-butyl ether (MTBE), diethyl ether and the like.

In the first step of the alternative process, before the enamine isadded to the boron-containing reducing agent/acid complex, a proticsolvent (for example, isopropanol, ethanol, methanol, water and thelike) can optionally be added to the boron-containing reducingagent/acid complex. Alternatively, the protic solvent can be mixed withthe enamine before the enamine is added to the boron-containing reducingagent/acid complex. The protic solvent is added in an amount of fromabout 0 to about 10 molar equivalents (based on the enamine). Apreferred protic solvent is isopropanol in the amount of about 7 molarequivalents.

The second step of the alternative process involves adding to thereaction mixture resulting from the first step (i.e., the reductionsubstrate) a complex of a borohydride reagent (for example, NaBH₄,LiBH₄, KBH₄, NaCNBH₃ and the like; preferably, NaBH₄) and a carboxylicacid (R₂₉ -COOH wherein R₂₉ is loweralkyl, haloalkyl, phenyl orhalophenyl) to provide 2 (i.e., 3 wherein R₈ is hydrogen). Theborohydride reagent/carboxylic acid complex is prepared by adding theacid to the borohydride reagent in an inert solvent.

In the second step of the alternative process, the preferred carboxylicacid is trifluoroacetic acid. In the second step of the alternativeprocess, the molar ratio of reduction substrate: borohydride reagent:carboxylic acid is 1: from about 1 to about 8: from about 1 to about 24.A preferred molar ratio of reduction substrate: borohydride reagent:carboxylic acid is 1: about 4: from about 4 to about 12. A mostpreferred molar ratio of reduction substrate: borohydride reagent:carboxylic acid is 1: about 4: about 5.

The second step of the alternative process can also be accomplished byadding to the reaction mixture resulting from the first step (i.e., thereduction substrate) a boron complexing agent such as mono-, di- ortri-ethanolamine, diaminoethane, diaminopropane, ethylene glycol,propylene glycol and the like, followed by the addition of a ketonereducing agent (for example, LiAlH₄, NaBH₄, NaBH₃ CN, LiBH₄, KBH₄,K(OiPr)₃ BH, Na(OMe)₃ BH and the like; preferably,NaBH₄) as a solid oras a solution of the ketone reducing agent in an inert solvent toprovide 7 (i.e., 3 wherein R₈ is hydrogen). Suitable inert solventsinclude dimethylformamide (DMF), dimethylacetamide, triglyme and thelike.

In this version of the second step of the alternative process, thepreferred boron complexing agent is triethanolamine and the preferredketone reducing agent is NaBH₄. The molar ratio of reduction substrate:boron complexing agent: ketone reducing agent is 1: from about 3 toabout 4: from about 2 to about 3. A preferred molar ratio of reductionsubstrate: boron complexing agent: ketone reducing agent is 1: about 3:about 2.5. A preferred solvent for the NaBH₄ solution isdimethylacetamide.

Compound 7 can be N-deprotected by hydrogenation (for example, with H₂and Pd/C or H₂ and Pd(OH)₂ or formic acid and Pd/C or ammonium formateand Pd/C and the like) to provide the compound of formula 3b wherein R₆,R₇ and R₈ are each hydrogen.

Alternatively, the free 5-amino group of compound 7 can be N-protected(for example, as the t-butyloxycarbonylamino group by reaction withdi-t-butyl dicarbonate or other activated t-butyloxycarbonyl esters orazides). The N-protecting groups on the 2- amino group can beselectively removed as described above to provide the compound offormula 3c wherein R₆ and R₇ are hydrogen and R₈ is an N-protectinggroup.

A preferred embodiment of the compound of formula 3c is the compoundwherein R₈ is t-butyloxycarbonyl. A preferred method for isolating andpurifying this compound involves crystallizing the compound as its saltwith an organic carboxylic acid. Examples of suitable organic carboxylicacids include succinic acid, fumaric acid, malonic acid, glutaric acid,cinnamic acid, malic acid, mandelic acid, oxalic acid, tartaric acid,adipic acid, maleic acid, citric acid, lactic acid and the like.

Preferred carboxylic acids are succinic acid and fumaric acid.

Using one or the other of the N-protected forms of the compound offormula 3, it is possible to selectively further functionalize eitherthe 2-amino group or the 5-amino group while the other amino group isN-protected.

An alternative method for preparing compound 7 from compound 4 is shownin Scheme III. In the process of Scheme III, if R₇ is R_(7a) OC(O)-,then R_(7a) is loweralkyl. Reaction of 4 with R₉ ONH₂ (R₉ is hydrogen,loweralkyl or benzyl) provides oxime 8. Reduction of the oxime 8 (forexample, with LiAlH₄ and the like) provides 7.

An alternative process for the preparation of 3 from 4 is shown inScheme IV. The free amino group of enamine 4 can be protected to givecompound 9 (R" is phenyl, susbstituted phenyl, loweralkyl, benzyloxy oralkoxy). Preferably, R₆ and R₇ are each benzyl and R" is t-butyloxy.Reaction of 9 with a ketone reducing agent (for example, lithiumaluminum hydride, lithium triethylborohydride or sodium borohydride andthe like) gives the alcohol 10. Hydrogenation of 10 with hydrogen and ahydrogenation catalyst (for example, platinum oxide, palladium hydroxideon carbon or platinum on carbon and the like) provides di-N-protected 3.Selective N-deprotection of di-N-protected 3 provides a mono-N-protected3a or 3c. Subsequent deprotection of the other amino group of themono-N-protected 3a or 3c provides the unprotected diaminoalcohol 3b.

An alternative process for the preparation of 3 from 9 is shown inScheme V. Reaction of 9 (R₆, R₇ and R" are defined as herein;preferably, R₆ and R₇ are benzyl and R" is t-butyloxy) with aboron-containing reducing agent such as 9-borabicyclo[3.3.1]nonane,(R)-B-isopinocampheyl-9-borabicyclo[3.3.1]nonane or(S)-B-isopinocampheyl-9-borabicyclo[3.3.1]nonane and the like, boranesolutions in complexing and noncomplexing solvents (for example, boranesolutions in diethyl ether, methyl t-butyl ether, dioxane, dioxolane ormethylene chloride and the like or mixtures thereof)or a BH₃ complexsuch as a borane ether complex (for example, borane-tetrahydrofurancomplex and the like), a borane sulfide complex (for example,borane-methylsulfide complex, borane-1,4-oxathiane and the like), or aborane phosphine complex (for example, borane-tributylphosphine complex,borane-triphenylphosphine complex and the like) and the like) providesketone 11. A preferred boron-containing reducing agent isborane-tetrahydrofuran complex. Reduction of ketone 11 with, forexample, LiAlH₄, NaBH₄, NaBH₃ CN, LiBH₄, KBH₄, K(OiPr).sub. 3 BH,Na(OMe)₃ BH and the like) provides di-N-protected 3. A preferred ketonereducing agent is LiAlH₄ or KBH₄. ##STR21##

The term "loweralkyl" as used herein refers to straight or branchedchain alkyl radicals containing from 1 to 6 carbon atoms including, butnot limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,-iso-butyl,sec-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl,2,2-dimethylpropyl, n-hexyl and the like.

The term "alkoxy" as used herein refers to --OR₁₀ wherein R₁₀ is aloweralkyl group.

The term "halo" as used herein refers to F, Cl, Br or l.

The term "haloalkyl" as used herein refers to a loweralkyl group inwhich one or more hydrogen atoms has been replaced with a halogenincluding, but not limited to, trifluoromethyl, trichloromethyl,difuoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl,2,2-dichloroethyl and the like.

The term "halophenyl" as used herein refers to a phenyl group in whichone, two, three, four or five hydrogen atoms have been replaced with ahalogen including, but not limited to, chlorophenyl, bromophenyl,fluorophenyl, iodophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 2,3,5-trichlorophenyl, 2,4,6-trichlorophenyl,2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl,2,4-dichloro-5-fluorophenyl, 2,3-difuorophenyl, 2,4-difuorophenyl,2,5-difuorophenyl, 2,6-difuorophenyl, 3,4-difuorophenyl,3,5-difuorophenyl, 2,3,5-trichlorophenyl, 2,4,6-trichlorophenyl,2,3,4-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl,2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2,3,4,5-tetrafluorophenyl,2,3,5,6-tetrafluorophenyl, pentafluorophenyl and the like.

Acid addition salts of the compounds of the invention can be derivedfrom reaction of an amine-containing compound of the invention with aninorganic or organic acid. These salts include but are not limited tothe following: acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, malonate,glutarate, malate, mandelate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, p-toluenesulfonate and undecanoate.

Examples of acids which may be employed to form acid addition saltsinclude such inorganic acids as hydrochloric acid, sulphuric acid andphosphoric acid and such organic acids as oxalic acid, maleic acid,succinic acid and citric acid, as well as the other acids mentionedabove.

The term "substantially pure" as used herein refers to a compound whichis contaminated by not more than 10% of any other stereoisomer(enantiomer or diastereomer), preferably by not more than 5% of anyother stereoisomer and most preferably by not more than 3% of any otherstereoisomer.

As used herein, the terms "S" and "R" configuration are as defined bythe IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem. (1976) 45, 13-30.

The following examples will serve to further illustrate the compoundsand processes of the invention.

EXAMPLE 1 (L)-N,N-Dibenzylphenvlalanine benzyl ester

A solution containing L-phenylalanine (161 kg, 975 moles), potassiumcarbonate (445 kg, 3220 moles), water (675 L), ethanel (340 L), andbenzyl chloride (415 kg, 3275 moles) was heated to 90°±15° C. for 10-24hours. The reaction mixture was cooled to 60° C. and the lower aqueouslayer was removed. Heptane (850 L) and water (385 L) were added to theorganics, stirred, and the layers separated. The organics were thenwashed once with a water/methanol mixture (150 L/150 L). The organicswere then stripped to give the desired product as an oil,which wascarried on in the next step without purification.

IR (neat) 3090, 3050, 3030, 1730, 1495, 1450, 1160 cm⁻¹, ¹ H NMR (300MHz, CDCl₃) δ7.5-7.0 (m, 20H), 5.3 (d, 1H, J=13.5 Hz), 5.2 (d, 1H,J=13.5 Hz), 4.0 (d, 2H, J=15 Hz), 3.8 (t, 2H, J=8.4 Hz), 3.6 (d, 2H,J=15 Hz), 3.2 (dd, 1H, J= 8.4, 14.4 Hz), ¹³ C NMR (300 MHz, CDCl₃)δ172.0, 139.2, 138.0, 135.9, 129.4, 128.6, 128.5, 128.4, 128.2, 128.1,128.1, 126.9, 126.2, 66.0, 62.3, 54.3, 35.6. [α]_(D) -79° (c=0.9, DMF).

EXAMPLE 2a 4-S-N,N-Dibenzylamino-3-oxo-5-phenyl-pentanonitrile

A solution containing the product of Example 1 (i.e., benzyl ester)(approx. 0.45 moles) in 520 mL tetrahydrofuran and 420 mL acetonitrilewas cooled to -40° C. under nitrogen. A second solution containingsodium amide (48.7g, 1.25 moles) in 850 mL tetrahydrofuran was cooled to-40° C. To the sodium amide solution was slowly added 75 mL acetonitrileand the resulting solution was stirred at -40° C. for more than 15minutes. The sodium amide/acetonitrile solution was then slowly added tothe benzyl ester solution at -40° C. The combined solution was stirredat -40° C. for one hour and then quenched with 1150 mL of a 25% (w/v)citric acid solution. The resulting slurry was warmed to ambienttemperature and the organics separated. The organics were then washedwith 350 mL of a 25% (w/v) sodium chloride solution, then diluted with900 mL heptane. The organics were then washed three times with 900 mL ofa 5% (w/v) sodium chloride solution, two times with 900 mL of a 10%methanolic water solution, one time with 900 mL of a 15% methanolicwater solution, and then one time with 900 mL of a 20% methanolic watersolution. The organics were stripped and the resulting materialdissolved into 700 mL of hot ethanol. Upon cooling to room temperature,the desired product precipitated. Filtration gave the desired product in59% yield from the L-phenylalanine. IR (CHCl₃) 3090, 3050, 3030, 2250,1735, 1600, 1490, 1450, 1370, 1300, 1215 cm⁻¹, ¹ H NMR (CDCl₃) δ7.3 (m,15H), 3.9 (d, 1H, J=19.5 Hz), 3.8 (d, 2H, J=13.5 Hz) 3.6 (d, 2H, J=13.5Hz), 3.5 (dd, 1H, J=4.0, 10.5 Hz), 3.2 (dd, 1H, J=10.5, 13.5 Hz), 3.0(dd, 1H, J=4.0, 13.5 Hz), 3.0 (d, 1H, J=19.5 Hz), ¹³ C NMR (300 MHz,CDCl₃) δ197.0, 138.4, 138.0, 129.5, 129.0, 128.8, 128.6, 127.8, 126.4,68.6, 54.8, 30.0, 28.4. [α]_(D) -95° (c=0.5, DMF).

EXAMPLE 2b Alternate preparation of4-S-N,N-Dibenzylamino-3-oxo-5-phenyl-pentanonitrile

To a flask was charged sodium amide (5.8 g, 134 mmol) under nitrogenfollowed by 100 mL of methyl t-butyl ether (MTBE). The stirred solutionwas cooled to 0° C. Acetonitrile (8.6 mL, 165 mmol) was added over 1minute. This solution was stirred at 5°±5° C. for 30 minutes. A solutionof (L)-N,N-dibenzylphenylalanine benzyl ester (25 g, 90% pure, 51.6mmol)in 125 mL of MTBE was added over 15 minutes and the resultingheterogeneous mixture was stirred at 5°±5° C. until the reaction wascomplete (approx. 3 hours). The reaction was quenched with 100 mL of 25%w/v aqueous citric acid and warmed to 25° C. before separating thelayers. The organics were then washed with 100 mL of H₂ O. The aqueouslayer was separated and the organics filtered and concentrated in vacuo.The residue was crystallized from 50 mL of ethanol to afford 13.8 g ofthe desired product as a white solid.

EXAMPLE 2c Alternate preparation of4-S-N,N-Dibenzylamino-3-oxo-5-phenyl-pentanonitrile

To a solution containing sodium amide (120 kg, 3077 moles), heptane(1194 L), and tetrahydrofuran (590 L) cooled to 0° C., was added asolution containing the product of Example 1 (i.e., benzyl ester)(approx. 975 moles), tetrahydrofuran (290 L), heptane (570 L), andacetonitrile (114 L). The addition was done maintaining the temperaturebelow 5° C. The combined solution was stirred at 0°±5° C. for approx.one hour before quenching with 25% citric acid solution (1540 L) toadjust the pH to 5.0-7.0. The upper organic layer was separated andwashed with 25% aqueous sodium chloride (715 kg), treated with activatedcarbon (2 kg), and stripped. The resulting residue was crystallized froma 55° C. ethanol/water solution (809 kg/404 kg). The solution was cooledto 0° C. prior to crystallizing to give approx. 215 kg of the desiredproduct.

EXAMPLE 3 Alternate preparation of4-S-N,N-Dibenzylamino-3-oxo-5-phenyl-pentanonitrile

To a 1 liter jacketed reaction flask equipped with thermometer, nitrogeninlet, pressure-equalized addition funnel and mechanical stirrer wascharged a solution of potassium t-butoxide (32 g, 0.289 mol, 3.0 equiv)in tetrahydrofuran (350 mL) and cooled to an internal temperature of-10° C. To this was added a solution of the product of Example 1 (i.e,benzyl ester) (42.0 g, 0.0964 mol, 1.0 equiv) in tetrahydrofuran (10 mL)and acetonitrile (15 mL, 0.289 mol, 3.0 equiv) via pressure-equalizedaddition funnel over a period of 20 minutes. During the addition, theinternal temperature increased to -5° C. The reaction (now orange andtransparent) mixture stirred an additional 30 min at -10° C. An aliquotremoved from the reaction mixture after the addition of the benzyl estersolution was quenched in 10% aqueous citric acid and partitioned betweenheptane was analyzed by HPLC and revealed no starting material remainedand the presence of the desired nitrile in 93% ee in favor of the Sisomer, Chiralpak AD column, 1 mL/min,. 10%/-propanol in heptane,monitored @205 nm). The contents of the reactor were allowed to warm to0° C. over 30 minutes. Citric acid (10% aqueous, 200 mL) was chargedfollowed by Heptane (100 mL) and the reaction contents allowed to warmto 20° C. The aqueous phase was separated and the organic phase waswashed with 10% aqueous sodium chloride solution (200 mL) and theaqueous phase separated. The organic phase was concentrated in vacuousing a 45° C. bath. n-Butanol (100 mL) was then charged anddistillation in vacuo was conducted until the contents were reduced byapproximately 10% by volume. The suspension resulting was allowed tocool to 20° C. with mechanical stirring and held at that temperature for18 hours. The solid was filtered and dried in vacuo at 45° C. The yieldof the first crop was 20.5 g (57%). The material was >98% pure by HPLC.

EXAMPLE 4 2-Amino-5-S-N,N-dibenzylamino-4-oxo-1,6-diphenylhex-2-ene

To a -5° C. solution of the nitrile product of Example 2 (90 Kg, 244moles) in tetrahydrofuran (288 L), was added benzylmagnesium chloride(378 Kg, 2M in THF, 708 moles). The solution was warmed to ambienttemperature and stirred until analysis showed no starting material. Thesolution was then recooled to 5° C. and slowly transferred to a solutionof 15% citric acid (465 kg). Additional tetrahydrofuran (85 L) was usedto rinse out the original container and the rinse was added to thecitric acid quench container. The organics were separated and washedwith 10% sodium chloride (235 kg) and stripped to a solid. The productwas stripped again from ethanol (289 L) and then dissolved in 80° C.ethanol (581 L)). After cooling to room temperature and stirring for 12hours, the resulting product was filtered and dried in a vacuum oven at30° C. to give approx. 95 kg of the desired productproduct. mp 101°-102°C., IR (CDCl₃) 3630, 3500, 3110, 3060, 3030, 2230, 1620, 1595, 1520,1495, 1450 cm⁻¹, ¹ H NMR (300 MHZ, CDCl₃) d 9.8 (br s, 1H), 7.2 (m,20H), 5.1 (s, 1H), 4.9 (br s, 1H), 3.8 (d, 2H, J=14.7 Hz), 3.6 (d, 2H,J=14.7 Hz), 3.5 (m, 3H), 3.2 (dd, 1H, J=7.5, 14.4 Hz), 3.0 (dd, 1H,J=6.6, 14.4 Hz), ¹³ C NMR (CDCl₃) d 198.0, 162.8, 140.2, 140.1, 136.0,129.5, 129.3, 128.9, 128.7, 128.1, 128.0, 127.3, 126.7, 125.6, 96.9,66.5, 54.3, 42.3, 32.4. [α]_(D) -147° (c=0.5, DMF).

EXAMPLE 5a (2S, 3S,5S)-5-Amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenyl-hexane

A. A suspension of sodium borohydride (6.6 kg, 175 moles) intetrahydrofuran (157 L) was cooled to less than -10°±5° C.Methanesulfonic acid (41.6 kg, 433 moles) was slowly added and thetemperature kept below 0° C. during the addition. Once the addition wascomplete, a solution of water (6 L, 333 moles), the product of Example 4(20 kg, 43 moles) and tetrahydrofuran (61 L) was slowly added whilemaintaining the temperature below 0° C. during the addition. The mixturewas stirred for not less than 19 h at 0°±5° C.

B. To a separate flask was added sodium borohydride (6.6 kg, 175 moles)and tetrahydrofuran (157 L). After cooling to -5°±5° C., trifluoroaceticacid (24.8 kg, 218 moles) was added while maintaining the temperaturebelow 15° C. The solution was stirred 30 min at 15°±5° C. and was thenadded to the reaction mixture resulting from step A, keeping thetemperature at less than 20° C. This was stirred at 20°±5° C. untilreaction was complete. The solution was then cooled to 10°±5° C. andquenched with 3N NaOH (195 kg). After agitating with tert-butyl methylether (162 L), the organic layer was separated and washed one time with0.5N NaOH (200 kg), one time with 20% w/v aqueous ammonium chloride (195kg), and two times with 25% aqueous sodium chloride (160 kg). Theorganics were stripped to give the desired product as an oil which wasused directly in the next step.

IR (CHCl₃) 3510, 3400, 3110, 3060, 3030, 1630, ¹ H NMR (300 MHz, CDCl₃)δ7.2 (m, 20H), 4.1 (d, 2H, J=13.5 Hz), 3.65 (m, 1H), 3.5 (d, 2H, J=13.5Hz), 3.1 (m, 2H), 2.8 (m, 1H), 2.65 (m, 3H), 1.55 (m, 1H), 1.30 (m, 1H),¹³ C NMR (300 MHz, CDCl₃) δ140.8, 140.1, 138.2, 129.4, 129.4, 128.6,128.4, 128.3, 128.2, 126.8, 126.3, 125.7, 72.0, 63.6, 54.9, 53.3, 46.2,40.1, 30.2.

EXAMPLE 5b Alternative Preparation of (2S, 3S,5S)-5-Amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenyl-hexane

A suspension of sodium borohydride (30 kg, 793 moles) in1,2-dimethoxyethane (1356 L) was cooled to less than -5° C.Methanesulfonic acid (192 kg, 1998 moles) was slowly added keeping thetemperature below 5° C. Once the addition was complete, a solution ofisopropanol (142 L, 1849 moles), the product of Example 4 (123 kg, 267moles), and 1,2-dimethoxyethane (311 L) was slowly added to theborohydride solution maintaining the temperature below 5° C. during theaddition. The mixture was stirred for not less than 12 h at 0°±5° C.

The reaction was then quenched with the addition of triethanolamine (118kg). The temperature of the reaction mixture was kept below 5° C. duringthe quench. A separate solution containing sodium borohydride (25 kg,661 moles) and dimethylacetamide (184 kg) was then added whilemaintaining the temperature below 10° C. The solution was stirred for 3hours at 10°±5° C. The solution was then quenched with water (1375 L)and agitated for 30 minutes. After mixing with tert-butyl methyl ether(1096 L), the organic layer was separated and washed one time with 3%NaOH (443 kg), one time with 20% w/v aqueous ammonium chloride (1492kg), and one time with 25% aqueous sodium chloride (1588 kg). Theorganics were stripped to give the desired product as an oil.

EXAMPLE 6 (2S, 3S, 5S-2,5-Diamino-3-hydroxy-1,6-diphenylhexanedihydrochloride

To a stirred solution of[2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane (20kg, 43.1 mol) in methanol (250 kg) was added an aqueous solution ofammonium formate (13.6 kg, 215 mol) in water (23 kg) and an aqueoussuspension of 5% wet palladium on carbon (4.0 kg, Degussa catalyst, E101NE/W, approximately 50-60 % water by weight). The suspension whichresulted was heated to reflux (70°±10 ° C.) for 6 hours and then cooledto room temperature. The suspension was filtered through a bed ofdiatomaceous earth and the cake was washed with methanol (2×30 kg). Thefiltrate was concentrated via vacuum distillation to an aqueous oil. Theaqueous residue was taken up in 1N NaOH (200 liters) and extracted withethyl acetate (155 kg). The organic product layer was washed with a 20%aqueous sodium chloride solution (194 kg) and then with water (97 kg).The ethyl acetate product solution was then concentrated to an oil undervacuum distillation. Isopropanol (40 kg) was then charged to the residueand again the solution was concentrated to an oil with vacuumdistillation. To the oil was charged isopropanol (160 kg) andconcentrated aqueous hydrochloric acid (20.0 kg). Thesuspension/solution was then heated to reflux for 1 hour and then slowlycooled to room temperature. The slurry was then stirred for 12-16 hours.The slurry was filtered and the cake was washed with ethyl acetate (30kg). The wet cake was resuspended in isopropanol (93 kg) and water (6.25kg) and heated to reflux for 1 hour with stirring. The reaction mixturewas then slowly cooled to room temperature and stirred for 12-16 hours.The reaction mixture was filtered and the wet cake was washed withisopropanol (12 kg). The solid was dried in a vacuum oven at 45° C. forapproximately 24 hours to provide 7.5 kg of the desired product. ¹ H NMR(300 MHz, CD₃ OD) δ7.40-7.15 (m, 10H), 3.8 (ddd, 1H, J=11.4, 3.7, 3.7Hz), 3.68-3.58 (m, 1H), 3.37 (ddd, 1H, J=7.5, 7.5, 3.5 Hz), 3.05-2.80(m, 4H), 1.95-1.70 (m, 2H), ¹³ C NMR (300 MHz, CD₃ OD) δ5135.3, 135.1,129.0, 128.9, 128.7, 128.7, 127.12, 127.07, 67.4, 57.1, 51.6, 38.4,35.5, 35.2.

EXAMPLE 7[2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane

To a solution of the[2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane(approx. 105 kg, 226 moles) in MTBE (1096 L), was added BOC Anhydride(65 kg, 373 moles) and 10% potassium carbonate (550 kg). This mixturewas stirred until reaction was complete (approx. 1 hour). The bottomlayer was removed and the organics were washed with water (665 L). Thesolution was then stripped to give the desired product as an oil. 300MHz ¹ H NMR (CDCl₃) δ1.40 (s,9H), 1.58 (s, 2H), 2.45-2.85 (m, 4H), 3.05(m, 1H), 3.38 (d, 2H), 3.6 (m, 1H), 3.79 (m, 1H), 3.87 (d, 2H), 4.35 (s,1H), 4.85 (s, broad, 1H), 7.0-7.38 (m, 20H).

EXAMPLE 8a [2S,3S,5S]-2-amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane.

To a stirred solution of[2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane(12 g, 21.3 mmol) in methanol (350 mL) was charged ammonium formate(8.05 g, 128 mmol, 6.0 eq) and 10% palladium on carbon (2.4 g). Thesolution was stirred under nitrogen at 60° C. for three hours and thenat 75° C. for 12 hours. An additional amount of ammonium formate (6 g)and 10% palladium on carbon (1.5 g) was added as well as 1 mL of glacialacetic acid. The reaction was driven to completion within 2 hours at areflux temperature. The reaction mixture was then cooled to roomtemperature and then filtered through a bed of celite. The filter cakewas washed with methanol (75 mL) and the combined flitrates wereconcentrated under reduced pressure. The residue was taken up in 1N NaOH(300 mL) and extracted into methylene chloride (2×200 mL). The combinedorganic layers were washed with brine (250 mL) and dried over sodiumsulfate. Concentration of the solution under reduced pressure providedthe desired product as a light colored oil which slowly crystallizedupon standing (5 g). Further purification of the product could beaccomplished by flash chromatography (silica gel, 5% methanol inmethylene chloride). 300 MHz ¹ H NMR (CDCl₃) δ1.42 (s, 9H), 1.58 (m,1H), 1.70 (m, 1H), 2.20 (s, broad, 2H), 2.52 (m, 1H), 2.76-2.95 (m, 4H),3.50 (m, 1H), 3.95 (m, 1H), 4.80 (d, broad, 1H), 7.15-7.30 (m, 10H).

EXAMPLE 8b [2S,3S,5S]-2-amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane succinate salt

To a solution of[2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane(approx.127 kg, 225 moles) in methanol (437 L), was added a methanolic (285 L)slurry of 5% palladium on carbon (24 kg). To this was added a solutionof ammonium formate (84 kg, 1332 moles) in methanol (361 L). Thesolution was heated to 75° C. for 6-12 hours and then cooled to roomtemperature. Solids were filtered from the reaction mixture using afilter coated with filtered (Celite) and the methanol was stripped fromthe reaction mixture using heat and vacuum (up to 70° C.). The residuewas dissolved in isopropyl acetate (4400 kg) with heat (40° C.) and thenwashed with a 10% sodium carbonate solution (725 kg), and finally withwater (665 L). Both of the washes were performed at 40° C. to keep theproduct in solution. The solvent was removed under vacuum with heat (upto 70° C.). Isopropyl alcohol (475 L) was then added and stripped off toremove residual solvents. Isopropanol (1200 L) was added to the residueand stirred until homogeneous. To this solution was added a solution ofsuccinic acid (15-40 kg) in isopropanol (1200 L). The solution jacketwas heated to 70° C. to dissolve all of the solids and then allowed toslowly cool to room temperature and stir for 6 hours. The solution wasthen filtered to give the desired product as a white solid (55-80 kg).mp: 145°-146° C. ¹ H NMR: (Me₂ SO-d₆, 300 MHz) δ0.97 (d, 3H, IPA), 1.20(s, 9H), 1.57 (t, 2H), 2.20 (s, 2H, succinic acid), 2.55 (m, 2H), 2.66(m, 2H), 2.98 (m, 1H), 3.42 (m, 1H), 3.70 (m, 1H), 3.72 (m, 1H, IPA),6.60 (d, 1H, amide NH), 7.0-7.3 (m, 10H).

¹ H NMR: (CD₃ OD, 300 MHz) δ1.11 (d, 3H, J=7 Hz, IPA), 1.29 (s, 9H),1.70 (m, 2H), 2.47 (s, 2H, succinic acid), 2.65 (m, 2H), 2.85 (m, 2H),3.22 (m,1H), 3.64 (m, 1H), 3.84 (m, 1H), 7.05-7.35 (m, 10H).

In a similar manner, the following salts of[2S,3S,5S]-2-amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexanewere prepared.

[2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane fumarate salt: mp: 157°-159° C.

¹ H NMR: (Me₂ SO-d₆, 300 MHz) d 0.98 (d, 8H, IPA), 1.20 (s, 9H), 1.57(t, 2H), 2.62 (m, 2H), 2.71 (m, 2H), 3.01 (m, 1H), 3.43 (m, 1H), 3.68(m, 1H), 3.72 (m, 3H), 6.47 (s, 1H, fumaric acid), 6.57 (d, 1 H, amideNH), 7.0-7.3 (m, 10H).

[2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane malonate salt: mp: 150°-152° C.

¹ H NMR: (Me₂ SO-d₆, 300 MHz) d 0.98 (d, 1H, IPA), 1.17 (s, 9H), 1.61(m, 2H), 2.65 (m, 2H), 2.66 (s, 1H, malonic acid), 2.81 (m, 2H), 3.31(m, 1H), 3.53 (m, 1H), 3.69 (m, 1H), 6.61 (d, 1H, amide NH), 7.0-7.3 (m,10H). 13C NMR: (Me₂ SO-d₆) d 28.2, 36.1, 38.5, 38.9, 39.8, 48.0, 54.6,65.3, 77.3, 125.8, 126.7, 127.8, 128.5, 129.2, 129.3, 136.5, 138.8,155.0, 171.5.

[2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexaneglutarate salt: mp: 162°-164° C.

¹ H NMR: (Me₂ SO-d₆, 300 MHz) d 0.98 (d, 6H, IPA), 1.21 (s, 9H), 1.55(m, 2H), 1.63 (m, 1H, glutaric acid), 2.25 (t, 2H, glutaric acid), 2.49(m, 2H), 2.67 (m, 2H), 2.84 (m, 1H), 3.39 (m, 1H), 3.72 (m, 1H), 3.73(m, 1H), 6.59 (d, 1H), 7.0-7.3 (m, 10H).

¹³ C NMR: (Me₂ SO-d₆) d 25.5, 28.2, 34.0, 48.5, 55.4, 62.0, 68.6, 77.0,125.6, 125.7, 127.8, 127.9, 129.1, 139.0, 139.5, 154.9, 174.5.

[2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexanetrans-cinnamate salt: mp: 164°-165° C.

¹ H NMR; (Me₂ SO-d₆, 300 MHz) d 1.21 (s, 9H), 1.57 (m, 2H), 2.52 (m,2H), 2.59 (m, 2H), 2.90 (m, 1H), 3.41 (m, 1H), 3.70 (m, 1H), 6.47 (d,1H, cinnamic acid), 6.59 (d, 1H), 7.0-7.3 (m, 12H), 7.33 (m, 3H), 7.42(d, 1H, cinnamic acid), 7.59 (m, 2H).

¹³ C NMR: (Me₂ SO-d₆) d 28.2, 48.3, 55.2, 68.3, 77.1, 101.8, 125.6,125.8, 127.8, 128.2, 128.8, 129.2, 134.9, 139.1, 139.2, 141.5, 166.0,168.3, 200.0.

[2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexaneL-malate salt: mp:152°-154° C.

¹ H NMR: (Me₂ SO-d₆, 300 MHz) d 0.99 (d, 3H, IPA), 1.20 (s, 9H), 2.24(dd, 1H, L-Malic acid), 2.40 (d, 1H, L-Malic acid), 2.48-2.78 (m, 3H),3.02 (m, 1H), 3.44 (m, 1H), 3.58 (m, 1H), 3.61 (m, 1H, IPA), 3.77 (dd,1H, L-Malic acid), 6.60 (d, 1H, amide NH), 7.0-7.3 (m, 10H).

¹³ C NMR: (Me₂ SO-d₆) d 25.5, 28.2, 48.3, 55.1, 61.8, 65.5, 67.3, 77.0,125.5,

[2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane S(+) mandelate salt; mp: 165°-167° C.

2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane R(-)mandelate salt: mp: 173°-175° C.

2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane oxalate salt: mp: 201-202

[2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphqnylhexane oxalate dihvdrate salt: mp: 206°-208° C.

[2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane D-tartrate salt: mp:187°-188° C.

EXAMPLE 9syn-(2S)-2-(N,N-dibenzyl)amino-5-benzyloxyimino-1,6-diphenyl-3-oxo-hexaneandanti-(2S)-2-(N,N-dibenzyl)amino-5-benzyloxyimino-1,6-diphenyl-3-oxo-hexane

A solution of 1.0 mg (2.17 mmol) of(2S)-2-(N,N-dibenzyl)amino-5-amino-1,6-diphenyl-3-oxo-4-hexene and 347mg of O-benzylhydroxylamine hydrochloride (2.17 mmol) in 50 ml ofacetonitrile was refluxed under N₂ atmosphere for 1 h. After most of theacetonitrile was removed in vacuo, the residue was treated with 20 ml ofsaturated aqueous NaHCO₃ and extracted with four 20 ml portions ofdichloromethane. The combined organic layers were dried over Na₂ SO₄ andconcentrated in vacuo to provide 1.24 g (100%) of the desired syn andanti mixture as a colorless oil. The syn-O-benzyloxime andanti-O-benzyloxime could be separated by silica gel chromatography using50% dichloromethane in hexane.

syn-O-benzyl oxime: ¹ H NMR (CDCl₃) δ2.85 (1H, dd, J=13.5, 4.5 Hz), 3.03(1H, d, J=16.5 Hz), 3.07 (1H, dd, J=13.5, 8.7 Hz), 3.44 (2H, q_(AB)),3.53 (1H, dd, J=9.2, 4.0 Hz), 3.55 (2H, d, J=13.8 Hz), 3.60 (1H, d,J=16.9 Hz), 3.69 (2H, d, J=13.8 Hz), 4.93 (2H, q_(AB)), 6.97-7.32 (25H,m). Mass spectrum: (M+H)⁺ =567.

anti-O-benzyl oxime: ¹ H NMR (CDCl₃) δ2.87 (1H, dd, J=13.5, 4.2 Hz),3.07 (1H, d, J=16.8 Hz), 3.08 (1H, dd, J=13.5, 8.7 Hz), 3.42 (1H, d,J=16.5 Hz), 3.46 (1H, dd, J=9.0, 4.5 Hz), 3.51 (2H, d, J=13.6 Hz), 3.60(2H, q_(AB)), 3.70 (2H, d, J=13.6 Hz), 5.04 (2H, s), 6.68-7.35 (25H, m).Mass spectrum: (M+H)⁺ =567.

EXAMPLE 10 Alternative Preparation of(2S,3S,5S)-2-(N,N-dibenzyl)amino-5-amino- 1,6-diphenyl-3-hydroxyhexane.

A solution of 100 mg (0.176 mmol) ofsyn-(2S)-2-(N,N-dibenzyl)amino-5-benzyloxyimino-1,6-diphenyl-3-oxo-hexanein 2 mL of tetrahydrofuran was treated with 0.882 ml (0.882 mmol) of 1Msolution of lithium aluminium hydride in tetrahydrofuran at 0° C. Thereaction mixture was then gradually warmed to ambient temperature andstirred for 15 h. The mixture was quenched with saturated aqueous Na₂SO₄ (0.25 ml) and the resulting precipitate was filtered off. Thefiltrate was concentrated and the residue was purified by silica gelchromatography using 2% methanol and 2% isopropylamine indichloromethane to provide 76.3 mg (93%) of the desired (2S,3S,5S)compound and two isomers (2S,3R,5R and 2S,3S,5R) in the ratio of 9.6: 1:0.7.

The reaction started from the syn and anti mixture gave the sameproducts, with a diasteriomer ratio of 8.0:0.6:1.

EXAMPLE 11(S)-2-t-butyloxycarbonylamino-5-N,N-dibenzylamino-1,6-diphenyl-4-oxo-2-hexene

To 9.21 gm (20 mmol) of the product of Example 4 and 0.37 gm (3 mmol)4-N,N-dimethylaminopyridine in 100 ml of methyl tert-butylether wasadded via syringe pump a solution containing 4.80 gm (22 mmol)di-tert-butyl carbonate in the same solvent (25 ml) over a period of 6h. An additional amount (3 ml) of methyl tert-butylether was then addedto complete the addition. After stirring at room temperature for 18 hthe reaction mixture was cooled with the aide of an ice water bath. Theresultant solid was collected by suction filtration and washed with cold(0° C.) methyl tert-butylether and hexane and dried under vacuum to give9.9 gm. of crude material as a white solid. The material thus isolatedwas disolved in a minimal amount of dichloromethane and purified byflash chromatography on silica gel. Elution of the column with a mixtureof hexane-ethyl acetate-dichloromethane (8:1:1) gave, afterconcentration of the appropriate fractions, 8.1 gm (72%) of the desiredN-Boc vinylogous amide. Mp. 191°-193° C. [α]_(D) 183.7° (c=1.05, CHCl₃).¹ H NMR (CDCl₃, δ): 11,68 (bs, 1H), 7.05-7.47 (m, 20H), 5.28 (s,1H),4.27 (d, J=16 Hz, 1H), 4.02 (d, J=16 Hz, 1H), 3.58 (m, 4H), 3.40 (m,1H), 3.11 (m, 1H), 2.90 (m, 1H), 1.48 (s, 9H).

EXAMPLE 12 Alternate preparation of(S)-2-t-butyloxycarbonylamino-5-N,N-dibenzylamino-1,6-diphenyl-4-oxo-2-hexene

A suspension of (S)-2-Amino-5-dibenzylamino-1,6-diphenyl-4-oxo-2-hexene(100.0 g, 0.217 mol) in 15% ethyl acetate/hexanes (2 liters) under N₂was warmed to about 40° C. The resulting solution was cooled to roomtemperature before adding 4.0 g (33 mmol) ofN,N-dimethyl-4-aminopyridine and 49.7 g (0.228 mol) of di-tert-butyldicarbonate. The reaction mixture was allowed to stir overnight at roomtemperature. (Ater approximately one hour, a white precipitate began toform.) The suspension was filtered and the precipitate was washed withhexanes to afford the desired product as colorless crystals. TLC: 25%ethyl acetate/hexanes R_(f) 0.38.

EXAMPLE 13 (2S,3S)-2-N,N-Dibenzylamino-5-t-butyloxycarbonylamino-3-hydroxy-1,6-diphenyl-hex-4-ene.

A 100 ml flask was equipped with magnetic stirrer and positive nitrogenpressure. The flask was charged with with the product of Example 11 (1g, 1.8 mmol) and anhydrous THF (10ml). The solution was chilled to 0° C.A 1M solution of LiAlH₄ in THF (1.8 ml, 1.8 mmol) was added. The coldbath was removed and the reaction was stirred at room temperature.Reaction was 80-90% complete after addition of the LAH. The reaction wasquenched using the Fieser workup (0.2 ml H₂ O; 0.2 ml 15% NaOH; 0.6 mlH₂ O). The organic solution of the product was dried over anhydroussodium sulfate and evaporated to provide the desired product as a whitefoam (˜70% yield). TLC: 25% EtOAc/hexane starting material Rf=0.55,product Rf=0.45. ¹ H-NMR (CDCl₃) δ7.37-7.10 m 20H; 6.78 br s 1H; 4.62 d1H; 4.50 s 1H; 4.18 dd 1H; 3.90 d 2H; 3.65 dd 2H; 3.40 d 2H; 3.00 m 2H;2.77 m 1H; 1.48 s 9H.

EXAMPLE 14 Alternate preparation of (2S,3S)-2-N,N-Dibenzylamino-5-t-butyloxycarbonylamino-3-hydroxy-1,6-diphenyl-hex-4-ene.

To a solution of 200 mg (0.36 mmole) of2S-dibenzylamino-3-oxo-5-t-butyloxycarbonylamino-1,6-diphenyl-hex-4-enein 8 mL of dry THF at -78° C. was added 1.4 mL of a 1M solution oflithium triethylborohydride. The solution was stirred at -78° C. for 1 hand quenched with water and extracted with ethyl acetate (3×50 mL). Theorganic layer was dried with anhydrous sodium sulfate and filtered.Concentration of the ethyl acetate solution in vacuo and purification ofthe crude residue by silica gel column chromatography (20% EtOAc/hexane)provided 125 mg of pure desired product and 65 mg of recovered startingmaterial. 300 MHz ¹ H NMR (CDCl₃): δ1.48 (s, 9H), 2.75 (m, 1H), 2.98 (m,2 H), 3.40 (d, J=12 Hz, 2H), 3.65 (AB q, J=15 Hz, 2H), 3.90 (d, J=12 Hz,2H), 4.17 (m, 1H), 4.48 (s, 1H), 4.62 (d, J=6.5 Hz, 1H), 6.77 (br s,1H), 7.10-7.35 (m, 20H).

EXAMPLE 15 (2S, 3S,5S)-2-N,N-Dibenzylamino-5-t-butyloxycarbonylamino-3-hydroxy-1,6-diphenylhexane.

To a suspension of 50 mg of platinum oxide in 12 mL of ethanol was added120 mg of the product of Example 14. The reaction mixture was shakenvigorously under a hydrogen pressure of approx. 60 psi using a Parrhydrogenation apparatus. After 15 h, the catalyst was filtered andwashed with 30 mL of ethanol. Solvent of the combined ethanol solutionwas evaporated in vacuo and the residue purified by silica gel columnchromatography (3% to 5% EtOAc/CH₂ Cl₂) to provide 10 mg of recoveredstarting material and 78 mg of desired product (70%). 300 MHz ¹ H NMR(CDCl₃): δ1.20 (m, 2H), 1.40 (s, 9H), 2.55-2.80 (m, 4H), 3.05 (m, 1H),3.47 (d, J=13.5 Hz, 2H), 3.60 (m, 1H), 3.80 (m, 1H), 3.90 (d, J=13.5 Hz,2H), 4.35 (s, 1H), 4.85 (br s, 1H), 7.02-7.30 (m, 20H).

EXAMPLE 16 (28.3S,5S)-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane.

To a suspension of 100 mg of 10% palladium hydroxide on charcoal in 10mL of isopropyl alcohol was added 73 mg of the product of Example 156.The mixture was shaken vigorously under a hydrogen pressure of approx.60 psi using a Parr hydrogenation apparatus for 18 h. The catalyst wasfiltered off and washed with 50 mL of isopropyl alcohol. The solvent wasevaporated in vacuo and the residue was purified by silica gel columnchromatography (5% to 10% MeOH/CH₂ Cl₂) to provide 36 mg of desiredproduct (72%). 300 MHz ¹ H NMR (CDCl₃): d 1.42 (s, 9H), 1.58 (m, 1H),1.70 (m, 1H), 2.20 (br s, 2H), 2.52 (m, 1H), 2.76-2.95 (m, 4H), 3.50 (m,1H), 3.95 (m, 1H), 4.80 (br d, 1H), 7.15-7.30 (m, 10H). Mass spectrum:(M+H)⁺ =385.

EXAMPLE 17 Alternative Preparation of (2S, 3S,5S)-2-N,N-Dibenzylamino-5-t-butyloxycarbonylamino-3-hydroxy-1,6-diphenylhexane.

A solution of the product of Example 11 (5 g, 8.9 mmol) indichloromethane (100 ml) and 1,4-dioxolane (100 ml) was cooled tobetween -10° and -15° C. and treated dropwise with 1M BH₃ THF (26.7 ml,26.7 mmol). The solution was stirred at this temperature for 3 hr. Theclear solution was quenched with excess methanol (20 ml) and stirred atroom temperature for 30 min. The solvent was removed in vacuo.

The white foam was dissolved in THF (75ml) and cooled to -40° C. Asolution of LAH (9 ml, 1M in THF, 9 mmol) was added dropwise. After 10min. the solution was quenched with water followed by dilute aqueousHCl. The organics were removed and the aqueous layer extracted withethyl acetate (3×20 ml). The combined organics were washed (saturatedaqueous bicarbonate followed by brine), dried (Na₂ SO₄), filtered andevaporated to afford 4.9 g (99%) of the desired product as a white foam.

Alternately, the white foam resulting from the BH₃ THF reaction step wasdissolved in MeOH (45 ml), cooled to +3° C. and treated portionwise withKBH₄ (1.44 g, 26.7 mmol). After addition of the last portion of KBH₄ thereaction was stirred for an additional 4 hours at +4° to +5° C. Thesolution was concentrated by 1/2 the volume in vacuo, diluted with 1/1hexane-EtOAc (70 ml) and quenched (with cooling, maintain temp. <30° C.)by adding a 10% solution of KHSO₄ to pH=about 5. NaOH (15% aqueous) wasadded to pH=12-13. The insoluble salts were removed by filtration, andthe filter cake washed 3 times with 7 ml 1/1 hexane/EtOAc. The flitrateand washes were transferred to a separatory funnel, diluted with 15 mlhexane and 15 ml H₂ O. The organics were removed and the aqueous layerwas extracted once with 20 mls (1/1) hexane-EtOAc. The combined organicswere washed (saturated brine), dried (Na₂ SO₄), filtered, and evaporatedto afford 5.2 g of the desired product which was used without furtherpurification in subsequent reactions. R_(f) 0.5 (25% EtOAc/hexane) 1HNMR (CDCl₃) δ7.37-7.10 (m 20H); 6.78 (br. s, 1H); 4.62 (d, 1H); 4.50 (s,1H); 4.18 (dd, 1H); 3.9 (d, 2H); 3.65 (dd, 2H); 3.40 (d, 2H); 3.00 (m,2H); 2.77 (m, 1H); 1.39 (s, 9H). MS (El) m/e565 (M+H).

EXAMPLE 18 Alternative Preparation of (2S, 8S,5S)-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane.

A solution of the product from Example 17 (150 gms, 250 mmol) dissolvedin absolute EtOH (2 liters) was treated with 10% Pd/C (1 8 gms,prewetted), followed by addition of ammonium formate (78.6 gms, 1.25moles) dissolved in H₂ O (200 ml). The resulting mixture was stirred atreflux for 2.5 hours. The mixture was cooled to room temperature andfiltered through a pad of infusorial earth (20 g). The filter cake waswashed 3 times with EtOH (70 ml each). The flitrate was concentrated invacuo. The residue was dissolved into EtOAc (1 L) and washed (1N NaOH,followed by H₂ O, followed by brine), dried (Na₂ SO₄), filtered andconcentrated in vacuo. to a constant weight of 95 gms. (99.2% oftheory). The light yellow solid (91.5 gms of the 95 gms) was slurried inhot heptane (600 ml) (steam bath) and treated with isopropanol (45 ml),and swirled to effect solution. The solution was allowed to slowly coolto room temperature over 3 hours, kept at room temperature for 2 morehours and filtered. The filter cake was washed 10 times with 9/1hexane-isopropanol (30 ml each) to give the desired product as anoff-white finely crystalline solid which was dried to constant weight of57.5 gms.

The crude product (20 gms) was recrystallized from hot 1 40 mlheptane/17 ml isopropanol. After letting the solution cool slowly toroom temperature, the mixture was let stand at room temperature for 2hours and then filtered. The filter cake was rinsed (5×15 ml (8/1)heptane/isopropanol) and dried to a constant weight of 18.5 gms.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed embodiments. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed is:
 1. A substantially pure compound of the formula:##STR22## wherein R₆ and R₇ are independently selected from ##STR23##wherein R_(a) and R_(b) are independently selected from hydrogen,loweralkyl and phenyl and R_(c), R_(d) and R_(e) are independentlyselected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo andphenyl; and ##STR24## wherein the naphthyl ring is unsubstituted orsubstituted with one, two or three substitutents independently selectedfrom loweralkyl, trifluoromethyl, alkoxy and halo; orR₆ is as definedabove and R₇ is R_(7a) OC(O)- wherein R_(7a) is loweralkyl or benzyl; orR₆ and R₇ taken together with the nitrogen atom to which they are bondedare ##STR25## wherein R_(f), R_(g), R_(h) and R_(i) are independentlyselected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyland R" is loweralkyl, alkoxy, benzyloxy or phenyl wherein the phenylring is unsubstituted or substituted with one, two or three substituentsindependently selected from loweralkyl, trifluoromethyl, alkoxy andhalo; or an acid addition salt thereof.
 2. The compound of claim 1 whichis (2S,3S)-2-N,N-dibenzylamino-5-t-butyloxycarbonylamino-3-hydroxy-1,6-diphenyl-hex-4-ene;or an acid addition salt thereof.